PROJECT SUMMARY Rapid Weight Gain (RWG; >+0.67 change in weight-for-age Z-score) during the first 6 months of life is a strong determinant of early life and persistent obesity, and cardiometabolic diseases. Obesity affects 18.5% of American children aged 2-19 years and 8.1% of those <2 years. While short sleep duration and poor sleep quality are important early risk factors for the development of childhood obesity and are major targets of national prevention efforts, their impact on early RWG is less understood. Sleep-wake patterns in infancy, such as the development of the 24-hr circadian sleep-wake rhythm, an important neurological milestone, may be especially important for influencing risk of RWG. Disruptions to circadian sleep-wake rhythmicity are associated with greater adiposity and its development primarily occurs in the first 6 months of life, the same critical, predictive timeframe as RWG. The human gut microbiome (GM) is also established during this time to promote growth through energy harvesting and metabolic signaling. Emerging data suggest that sleep may alter the GM and infant metabolism, which ultimately may impact obesity. To date, most GM research has focused on the independent effects of vaginal vs. cesarean birth delivery, antibiotic use, and breastfeeding vs. formula feeding on childhood obesity risk. However, evidence is limited on if sleep-wake pattern and GM development interact to influence RWG. Broadening our understanding of the GM role in obesity risk in early life to include the establishment of sleep- wake patterns will improve our ability to intervene at a young age and prevent the onset of obesity. Therefore, we propose to prospectively follow 192 mother-infant pairs prenatally through 12 months (3 weeks, 8 weeks, and 3, 6, 9 and 12 months) of life and assess the magnitude and timing of infant sleep-wake patterns and GM development as predictors of RWG. This project will implement a novel conceptual framework that incorporates the GM and sleep-wake patterns as metabolic contributors for RWG. The underlying theoretical and analytical framework of this work will be based on the Ecological Model of Growth (EMG) that focuses on child, maternal, family, and environmental factors that contribute to a child?s growth and combines human ecology and epidemiology to evaluate broader interactions among these factors that influence child health outcomes. EMG factors will be included as covariates in models of sleep and GM development on RWG. Our study will address the following aims: 1- Investigate associations of infant sleep-wake patterns with subsequent RWG at 6 months and weight gain at 12 months using time-varying effect models; 2- Investigate associations of GM development with RWG at 6 months and weight at 12 months; and 3- Evaluate whether temporal interactions exist between infant sleep-wake patterns and GM development, and if these relations influence RWG. Project findings will inform future clinical interventions that include sleep and GM approaches to reduce the risk of RWG in infancy. This pipeline of work will ultimately lead to the development of evidence-based guidelines for sleep and GM development to prevent obesity through the identification of crucial developmental time intervals for RWG.